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CDK phosphorylation of TRF2 controls t-loop dynamics during the cell cycle

Research output: Contribution to Journal/MagazineJournal articlepeer-review

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  • G. Sarek
  • P. Kotsantis
  • P. Ruis
  • D. Van Ly
  • P. Margalef
  • V. Borel
  • X.-F. Zheng
  • H.R. Flynn
  • A.P. Snijders
  • D. Chowdhury
  • A.J. Cesare
  • S.J. Boulton
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<mark>Journal publication date</mark>21/11/2019
<mark>Journal</mark>Nature
Volume575
Number of pages5
Pages (from-to)523-527
Publication StatusPublished
Early online date13/11/19
<mark>Original language</mark>English

Abstract

The protection of telomere ends by the shelterin complex prevents DNA damage signalling and promiscuous repair at chromosome ends. Evidence suggests that the 3′ single-stranded telomere end can assemble into a lasso-like t-loop configuration1,2, which has been proposed to safeguard chromosome ends from being recognized as DNA double-strand breaks2. Mechanisms must also exist to transiently disassemble t-loops to allow accurate telomere replication and to permit telomerase access to the 3′ end to solve the end-replication problem. However, the regulation and physiological importance of t-loops in the protection of telomere ends remains unknown. Here we identify a CDK phosphorylation site in the shelterin subunit at Ser365 of TRF2, whose dephosphorylation in S phase by the PP6R3 phosphatase provides a narrow window during which the RTEL1 helicase can transiently access and unwind t-loops to facilitate telomere replication. Re-phosphorylation of TRF2 at Ser365 outside of S phase is required to release RTEL1 from telomeres, which not only protects t-loops from promiscuous unwinding and inappropriate activation of ATM, but also counteracts replication conflicts at DNA secondary structures that arise within telomeres and across the genome. Hence, a phospho-switch in TRF2 coordinates the assembly and disassembly of t-loops during the cell cycle, which protects telomeres from replication stress and an unscheduled DNA damage response.